The candidate is a MD-PhD with training in internal medicine, cardiology, and molecular biology. He is currently performing basic research in cardiac development while completing his cardiology fellowship. He is seeking intensive mentored research with the goal to become an independent academic physician scientist. At the time of the award he will be in the Cardiology division at the University of Pennsylvania. This proposal focuses on Toto and Lbx2, two novel murine homeobox genes recently discovered by the candidate involved in heart development. Research on cardiac development will provide insights into the pathogenesis, diagnosis, and treatment of cardiac disease. The gene Toto demonstrates cardiac specificity in early development similar to Nkx-2.5/Csx, a homeobox gene critical for cardiogenesis. Toto is the first member of a new unusually small molecular weight class of homeobox genes. The candidate proposes that Toto may be important for cardiogenesis. Lbx2, related to the ladybird genes important in Drosophila organogenesis, is strongly expressed in the nodose ganglion that develops to form the autonomic innervation of the heart. The candidate proposes that Lbx2 may be important in the development of the nervous innervation of the heart. Specific aims are: l. Analysis of Toto : This will include RNA and protein expression analysis, analysis of potential DNA binding properties, analysis of potential physical or genetic interactions with other cardiac transcription factors, identification of cardiac-specific enhancers, targeted disruption of Toto in transgenic mice, and genomic mapping to identify relationships with human disease. 2. Analysis of Lbx2: This will include RNA and protein expression analysis, identification of tissue-specific enhancers, fate-mapping of Lbx2 precursor cells destined to innervate the heart using a Cre-lox approach, and targeted disruption of the Lbx2 gene in transgenic mice.